Role of gut microbiota in the pathogenesis of colorectal cancer; a review article

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Lifestyle is identified as one of the most important risk factors for CRC, especially in sporadic colorectal cancer. The natural composition of the gut microbiota changes rapidly during the first decade of life. Maintaining homeostasis in the gut is essential as structural and metabolic functions of the commensal microbiota inhibit gut colonization of pathogens. Dysbiosis, imbalance in function or structure of gut microbiota, has been associated with a variety of diseases, such as colorectal cancer. The aim of this review was to investigate the possible links between the dysbiosis in gut microbiota and colorectal cancer, and the potential role of anaerobic gut microbiota in the pathogenesis of colorectal cancer. Based on this review, various studies have shown that some of the gut microbiota such as anaerobic bacteria significantly increased in CRC patients, but we suggest more investigations are required to assess the importance of these bacteria and their metabolites in the pathogenesis of CRC are required.


Introduction
Colorectal cancer (CRC) is one of the top three most frequently diagnosed cancers worldwide, with nearly 1.4 million new cases diagnosed in 2012. More than 50 percent of colorectal cancer cases were reported in developed countries with the least incidence in Africa and Asia (1). Although developing countries are lowrisk countries for CRC, particularly among the older population, but the age standardized rate within the young population in some Asian countries such as Iran and Pakistan, is as the same as US inhabitants (2,3). Despite extensive research exact etiology for CRC is still unknown, but genetic and environmental factors have been implicated as disease' risk factors. The environmental factors such as diet, antibiotic therapy, hospitalization, chemical exposure, and contact with the vaginal microbiota during birth, could be a connection between life style and accumulation of mutation in host (6)(7)(8). Gut microbiota are predominantly strict anaerobes, including Bacteroides, Eubacterium, Bifidobacterium, Fusobacterium, Peptostreptococcus, and Atopobium, while facultative anaerobes, such as Enterococci, Lactobacilli, Enterobacteriaceae, and Streptococci, form a minor portion of inhabitants (9). Maintaining this structure is essential for the gut hemostasis because structural and metabolic functions of the commensal microbiota inhibit gut colonization of pathogens. Microbiota participate in the production of short chain fatty acids and proteolytic fermentation by fermentation of anaerobic carbohydrate. Short chain fatty acids elaborate butyrate, propionate and acetate, used as a source of energy in gut and helps to proliferation and differentiation of intestinal epithelial cells (10). Dysbiosis, imbalance in function or structure of gut microbiota, has been associated with a variety of diseases, such as inflammatory bowel disease, obesity, colitis, and colorectal cancer (11)(12)(13)(14)(15). Although the gut microbiota have long been considered commensal residents in the gut, recent studies have demonstrated that microbiota may contribute to CRC pre-carcinogenesis (16). In certain conditions the intestinal microbiota may be linked to an increase in the risk of carcinogenesis and promote tumor growth via various mechanisms ( Figure 1) (9). The relationship between cancer and microorganisms has been demonstrated in some organs, with the most wellknown example which is the relationship between Helicobacter pylori and gastric cancer and mucosaassociated lymphoid tissue lymphoma or papillomavirus and cervical cancer (17,18). Hence, there is much interest in understanding the composition of the gut microbiota in CRC patients in comparison to the healthy population as this knowledge may help develop new therapeutic methods for microbiota manipulation in benefit of the hosts health and disease prevention strategies. The aim of this review is to present the possible links between dysbiosis in the gut microbiota and colorectal cancer, and discuss the potential role of gut microbiota in the pathogenesis of colorectal cancer.

Methods
Searches were performed in PubMed, Medline, Google scholar, for articles published in English, and other bibliographic references and appropriate sources such as SID and Magiran for Persian-language journals from 2000 to December 2017 using the following keywords alone or in combination: "anaerobic," " microbiota," "pathogenesis," "colorectal cancer," "microbiome," "microbiota," and "dysbiosis." However, according to our explorer, no Persianlanguage papers were found. In total, 141 studies were published regarding the microbiota composition in colorectal cancer and based on the study scopes, we categorized all the papers into four major categories including gut microbiota colonization, frequency of gut microbiota, microbiota influence, and inflammatory Pathways.

Gut microbiota in colorectal cancer patients
Several studies have shown that numerous bacterial species appear to be associated with the pathogenesis of CRC and recent studies have provided a mechanism for the participation of gut microbiota in the progress of CRC (14,(19)(20)(21)(22) (24).

Frequency and pathogenesis of gut microbiota
Recent investigations have confirmed strong relations between the development of colorectal cancer and gut microbiota . According to global investigations, the most predominant species of the adult health intestinal microbiota are Bacteroidetes and Firmicutes followed by Actinobacteria, Proteobacteria, and Verrucomicrobia but the composition and frequency of following microbiota changed in CRC patients (25). Intestinal microbiota can contribute to carcinogenesis through production of secondary metabolites, such as reactive oxygen intermediates that caused DNA damage, or direct effects on cell transformation through the production of genotoxin. Different bacterial species such as Bacteroides fragilis,  (59). C. septicum normally grows in soil and does not represent part of the normal bowel flora but there is no clear mechanism to explain the frequent association between C.septicum infection and colon cancer (31,33).
S. bovis/gallolyticus bacteria were found in 2.5-15% of  (36). S. bovis/gallolyticus could colonize and grow in colorectum tissues via collagen-binding and histone-like protein A to collagen I, IV, fibronectin, fibrinogen in colon tissues (35). The activity of present microbiota causes severe inflammatory response by inducing inflammatory and angiogenic cytokines in colorectum tissues and leading to the development or proliferation of colorectal cancer (3).
In a study by Sobhani et al, 179 subjects including 60 colorectal cancer and 119 healthy individuals underwent colonoscopy and the results showed higher levels of Bacteroides/Prevotella in patients with colorectal cancer (23). Entrotoxigenic, Bacteroides fragilis increased in fecal samples of CRC patients. B. fragilis degraded the E-cadherin protein and activated nuclear beta-catenin signaling and induces c-Myc expression and cellular proliferation (30,60).
In a study by Gao et al. no (70). There is also another hypothesis that direct and indirect production of RONS by some strains could participate in tumorigenesis in the colon (71).
While E. coli is a commensal microbe of the human gut, several surveys have verified a strong association between mucosa-adherent E. coli and CRC (42)(43)(44). In 2004 Martin et al. reported that more than 70% of mucosa samples of CRC patients were inhabited by E.coli (42). Majority of E. coli isolated from CRC patients harbors the pks genomic island that is responsible for the synthesis of colibactin. Colibactin is another bacterial-derived genotoxin that can interference with the cell cycle and promote proliferation of epithelial cells via DNA damage, mutation and genomic instability, subsequently and, tumor growth (44).

Colon cancer and inflammatory pathways
As mentioned, increased gut microbiota release inflammatory agents via the inflammatory pathway and therefore promote the change of normal cells to cancerous cells. On the other hand, intestinal inflammation as observed in inflammatory bowel disease (IBD) is a risk factor for the development of CRC (72). Increasing evidence suggests that inflammation-associated pathways also contribute to CRC development in the absence of clinically overt intestinal inflammation. Thus, signaling pathways with central roles in myeloid and lymphoid cells, such as those associated with signal transducer and activator of transcription 3 (STAT3) and nuclear factor (NF)-κB, are also active in the transformed intestinal epithelium and promote tumor development (73,74).
A study by Wang et al. has recently shown a critical role of the microbiota, and its TLR-dependent recognition in intestinal tumor progress in human and rodents (75). Intestinal microbiota are also known to be involved in the initiation and development of colorectal cancer, which is a risk factor for inflammatory bowel disease.
The investigations confirmed profound modifications in the gut microbiota before or during the progression of colorectal cancer (9). Intestinal microbiota-dependent nutritional or lifestyle intermediation beside colorectal carcinoma deserve additional research. The result of different studies advocate that fecal microbiome-based approaches might be valuable for prompt diagnosis and treatment of colorectal cancer.

Conclusion
According to the presented studies, more prevalent gut microbiota variations in the fecal and biopsy samples of CRC patients were Fusobacterium, Porphyromonas, Bacteroidetes and Prevotella. (Table   1, 2). However, it seems that there is no difference between bacteria variation in developed and developing countries. Therefore, the strong association between the gut microbiota and CRC is evident, but several questions remain unanswered. As previously declared, the gut microbiota acts as a key role in the development of CRC through numerous mechanisms, comprising genotoxin, metabolism and inflammation. Thus, studies have provided supportive data that modifications in gut microbiota structure could induce a host immune response and plays a critical part in intestinal epigenic mechanisms of the host.
The studies that are discussed in this review did not highlight the classification of tumors according to their molecular phenotype and it is not clear why some adenomas growth to malignancy, while others are stable or even regress. According to investigations, a greater abundance of Fusobacterium was detected in cancer tissues than in normal tissues. Thus, the increased abundance of Fusobacterium could be linked with high risk of CRC. Therefore, we recommended future studies should consider the heterogeneity of CRC tumors by focusing

Conflict of interests
The authors declare that they have no conflict of interest.